Erythromycins A through D, represented by formula (E),
______________________________________ ##STR2## (E) Erythromycin R.sup.a R.sup.b ______________________________________ A --OH --CH.sub.3 B --H --CH.sub.3 C --OH --H D --H --H ______________________________________
are well-known and potent antibacterial agents, used widely to treat and prevent bacterial infection.
Some erythromycin derivatives have use as prokinetic agents. For example, an erythromycin B derivative, having formula I below: ##STR3## has been described as a prokinetic agent having use in the treatment of gastrointestinal motility disorders (see P. A. Lartey et al., J. Med Chem., 38 (1793-1798 (1995); and R. Faghih, et al., PCT application WO 9313780, published Jul. 22, 1993). U.S. Pat. No. 5,578,579 describes 4"-deoxyerythromycin derivatives having prokinetic activity.
The first step of the process for preparing these prokinetic compounds requires the N-demethylation step to obtain a compound having the formula: ##STR4## wherein R.sub.b is H or OH. The N-demethyl-erythromycin derivatives having the above formula are obtained by the process described in issued U.S. application Ser. No. 08/754,867. The process disclosed therein involves preparation of 3'-N-demethyl-erythromycin derivatives by step-wise addition of iodine in a pH-adjusted solution from 40.degree. C. to 70.degree. C. U.S. Pat. No. 5,578,579 describes a process of making N-demethyl-N-alkyl erythromycin derivatives wherein a 3'-N-dimethyl hemiketal derivative is first treated with iodine in the presence of a suitable base, such as sodium acetate, and then reacted with an alkyl halide and a hindered base. Alternatively, U.S. Pat. No. 3,725,385, issued Apr. 3, 1973, describes a process in which erythromycin derivatives are demethylated by a one-step treatment with a single addition of iodine in a pH-adjusted solution from -10.degree. C. to 50.degree. C.
Previous methods of N-alkylating the N-demethyl-erythromycin derivatives to obtain the prokinetic compound of formula (I) often result in formation of a quaternary salt which prevents completion of the reaction process and reduces yield of the N-demethyl-N-alkyl product.
Therefore, there continues to be a need to provide a rapid, efficient method of preparing the N-demethyl-N-alkyl erythromycin derivatives to ensure more efficient synthesis and wider availability of the desired prokinetic agents.